Western life style has spurred the growth of numerous obesity related disorders including metabolic syndrome, type 2 diabetes and certain types of cancers to epidemic proportions. Maintaining cellular energy is a basic biological need mediated in part through amp-activated protein kinase (AMPK), therefore controlling cellular energy metabolism can play a role in treating metabolism related disorders. Indeed, AMPK regulation has been a proposed target of pharmaceutical companies, with no major clinical successes yet. Our proposal seeks to identify novel small molecules that interact with the regulatory fragment of AMPK, rather than the traditional approach of targeting the AMPK kinase domain. Currently available chemical probes/tool compounds for AMPK lack the selectivity for AMPK and hit numerous other kinases due to conserved ATP-binding kinase domains throughout the kinome. Our approach has the potential to deliver selective AMPK regulation through the non-canonical regulatory domain that can have clinical translational potential in the treatment of human diseases.